Alcohol and nicotine codependence-associated DNA methylation changes in promoter regions of addiction-related genes

Abstract

Altered DNA methylation in addiction-related genes may modify the susceptibility to alcohol or drug dependence (AD or ND). We profiled peripheral blood DNA methylation levels of 384 CpGs in promoter regions of 82 addiction-related genes in 256 African Americans (AAs) (117 cases with AD-ND codependence and 139 controls) and 196 European Americans (103 cases with AD-ND codependence and 93 controls) using Illumina’s GoldenGate DNA methylation array assays. AD-ND codependence-associated DNA methylation changes were analyzed using linear mixed-effects models with consideration of batch effects and covariates age, sex, and ancestry proportions. Seventy CpGs (in 41 genes) showed nominally significant associations (P < 0.05) with AD-ND codependence in both AAs and EAs. One CpG (HTR2B cg27531267) was hypomethylated in AA cases (P = 7.2 × 10−5), while 17 CpGs in 16 genes (including HTR2B cg27531267) were hypermethylated in EA cases (5.6 × 10−9 ≤ P ≤ 9.5 × 10−5). Nevertheless, 13 single nucleotide polymorphisms (SNPs) nearby HTR2B cg27531267 and the interaction of these SNPs and cg27531267 did not show significant effects on AD-ND codependence in either AAs or EAs. Our study demonstrated that DNA methylation changes in addiction-related genes could be potential biomarkers for AD-ND co-dependence. Future studies need to explore whether DNA methylation alterations influence the risk of AD-ND codependence or the other way around.

Epigenomes in Cardiovascular Disease

“… 226 Genetic variability contributes to chromatin accessibility (measured via FAIRE-seq) in the basal state and following complex metabolic changes, such as those accompanying high-fat diet. 227 Human studies in ethnically diverse populations have revealed DNA methylation variation associated with nicotine and alcohol dependence (and the codependency between these forms of addiction) 228 although no evidence of inheritance or precedence of the phenotypes by the epigenetic features was demonstrated. In addition to the obvious prognostic and diagnostic potential of genomic and epigenomic measurements in the clinical arena (the practical considerations of which are discussed in detail elsewhere 229 , 230 ), it is noteworthy that tools for reducing epigenomic treatment to practice have begun to emerge (Figure 7 ).…”

DRD2 methylation is associated with executive control network connectivity and severity of alcohol problems among a sample of polysubstance users

“…methylation has yet to be investigated extensively in the context of AUD phenotypes, Hillemacher and colleagues (Hillemacher, Frieling, Hartl, Wilhelm, Kornhuber & Bleich 2009) demonstrated that lower D2 methylation was associated with abstinence among individuals with a history of pathologic gambling (Hillemacher et al, 2015), which shares common neural mechanisms with substance use disorders (Potenza 2008). Furthermore, among a sample of alcohol and nicotine dependent patients, methylation of the DRD2 gene was associated with alcohol and nicotine METHYLATION AND CONNECTIVITY codependence, along with methylation of additional addiction-related genes (Xu, Wang, Kranzler, Gelernter & Zhang 2017). Finally, Bidwell and colleagues (2018) found an association between DRD2 methylation and neural correlates of reward among problem alcohol users.…”

Epigenome-Wide Association Study and Multi-Tissue Replication of Individuals With Alcohol Use Disorder: Evidence for Abnormal Glucocorticoid Signaling Pathway Gene Regulation

“…Recent availability of DNA methylation array capture for comprehensive genome-wide profiling, has made it possible to conduct epigenome-wide association studies (EWASs). Only a few EWAS for AUD exist, but they are limited by small sample sizes, low array-capture, tissue types, inconsistent analysis strategy, and data interpretation [15][16][17][18][19][20][21][22][23][24][25]. Consequently, no universal DNA methylation loci for AUD have been identified; however, recent data suggest multiple loci associated with mild-moderate alcohol consumption [26] and interesting new targets for AUD [27].…”